Abstract: Congenital cytomegalovirus (CMV) transmission is the leading infectious cause of brain damage and hearing loss, affecting 1-2% of all live births (40,000 infants) in the U.S. annually. Up to 25% of infants who acquire CMV in utero following primary maternal infection develop long term virus- associated sequelae, including hearing loss, ocular defects, seizures, and cognitive deficits. Because of the public health impact and economic benefits of preventing congenital CMV transmission, development of a maternal CMV vaccine has been listed as a top priority by the Institute of Medicine. However, a limited understanding of how natural CMV immunity protects against symptomatic congenital CMV transmission and the lack of a relevant animal model, have hindered vaccine design. Therefore, there is an urgent need for multipronged, innovative investigations of immune responses that are protective against in utero CMV transmission in both human cohorts and relevant animal models. Elucidation of the maternal immune responses critical for protection against congenital CMV disease is vital to the design of immunologic interventions that will prevent CMV-associated brain damage and hearing loss. Primary infection of CMV-seronegative rhesus monkeys with rhesus CMV (rhCMV) has been used to investigate CMV pathogenesis. Further, fetal rhCMV inoculation leads to virus-associated neurologic sequelae similar to that of human congenital CMV infection. Therefore, I propose primary systemic infection of rhCMV-seronegative, pregnant rhesus monkeys as a model of congenital CMV transmission which can be used to dissect the roles of adaptive immune responses in containment of intrauterine CMV replication. Further, I propose detailed assessment of maternal cellular and humoral immune responses in mothers whose infants do and do not develop neurologic sequeale following primary maternal CMV infection, defining immune targets of a maternal CMV vaccine. I am uniquely well-suited to lead this multifacited approach towards the rational design of a maternal CMV vaccine, given my rigorous training in immunology and pediatric infectious diseases, clinical and research specialty in transmission of neonatal viral pathogens, and proven track record for designing and implementing nonhuman primate and human cohort studies. Taken together, these bold investigations of maternal immune protection against symptomatic congenital CMV infection in both a relevant nonhuman primate model and a large cohort of women screened for primary CMV transmission will speed the development of an effective maternal CMV vaccine, an intervention that will greatly reduce the prevalence of childhood neurologic deficits and hearing loss in our population. Public Health Relevance: Congenital CMV infection is the leading infectious cause of neurologic deficits and hearing loss in children, complicating 40,000 births in the U.S. annually. The protection of the developing fetus from CMV infection will require protective maternal CMV-specific immune responses similar to that provided by natural immunity following CMV infection. Elucidation of the maternal immune correlates of protection against congenital CMV transmission and disease is vital to the design of effective maternal vaccine strategies in preventing CMV-associated brain damage and hearing loss.